What Level of Blood Pressure (BP) should be Treated? Comments on the New Guidelines

Reporter: Aviva Lev-Ari, PhD, RN

ACC: 130/50 vs 140/90

Last year, the American Heart Association, the American College of Cardiology and many other cardiology organizations announced that the threshold for identifying hypertension had been officially lowered. The threshold for diagnosing and treating hypertension was now 130/80.

The document relies in part on the findings of the SPRINT trial, but no one really understands the blood pressures in that study. Strangely, the document applies its recommendations to people who were not even represented in the SPRINT trial. For example, it applies its recommendations to those with heart failure, even though there is no scientific basis for doing so.

Nevertheless, suddenly, 46% of Americans had hypertension. On the previous morning, 32% had the disease. Within 24 hours, millions of people were given a new label.

Furthermore, millions of people who thought they had well-controlled blood pressure (because it was below 140/90) now learned that they needed to do more to bring their blood pressures down.

In December, the American Academy of Family Physicians (AAFP) said they were not endorsing the new hypertension guideline.

American College of Physicians which proposed a target systolic blood pressure of 150 for people who were 60 years or older. Earlier this week, the ACP doubled down, issuing a statement criticizing the lower threshold.

The Fake Hypertension War – Medical politics and mud fights

Packer recently consulted for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cardiorentis, Daiichi Sankyo, Gilead, Novo Nordisk, Relypsa, Sanofi, Takeda, and ZS Pharma. He chairs the EMPEROR Executive Committee for trials of empagliflozin for the treatment of heart failure. He was previously the co-PI of the PARADIGM-HF trial and serves on the Steering Committee of the PARAGON-HF trial, but has no financial relationship with Novartis.

2017 Guideline for the Prevention, Detection, Evaluation and Management of High Blood Pressure in Adults – A REPORT OF THE American College of Cardiology/ American Heart Association Task Force on Clinical Practice Guidelines

Reporter: Aviva Lev-Ari, PhD, RN

The new Hypertension Guideline changes the definition of hypertension, which is now considered to be any systolic BP measurement of 130 mm Hg or higher—or any diastolic BP measurement of 80 mm Hg or higher.

The “genetically instrumented” measure of high BMI exposure — calculated based on 93 single-nucleotide polymorphisms associated with BMI in prior genome-wide association studies — was associated with the following risks (odds ratios given per standard deviation higher BMI):

Hypertension (OR 1.64, 95% CI 1.48-1.83)

Coronary heart disease (CHD; OR 1.35, 95% CI 1.09-1.69)

Type 2 diabetes (OR 2.53, 95% CI 2.04-3.13)

Systolic blood pressure (β 1.65 mm Hg, 95% CI 0.78-2.52 mm Hg)

Diastolic blood pressure (β 1.37 mm Hg, 95% CI 0.88-1.85 mm Hg)

However, there were no associations with stroke, Donald Lyall, PhD, of the University of Glasgow, and colleagues reported online in JAMA Cardiology.

“The main advantage of an MR approach is that certain types of study bias can be minimized,” the team noted. “Because DNA is stable and randomly inherited, which helps to mitigate errors from reverse causality and confounding, genetic variation can be used as a proxy for lifetime BMI to overcome limitations such as reverse causality and confounding, a process that hampers observational analyses of obesity and its consequences.”

Abstract

Hypertension involves remodelling and inflammation of the arterial wall. Interactions between vascular and inflammatory cells play a critical role in disease initiation and progression. T effector and regulatory lymphocytes, members of the adaptive immune system, play contrasting roles in hypertension. Signals from the central nervous system and the innate immune system antigen-presenting cells activate T effector lymphocytes and promote their differentiation towards pro-inflammatory T helper (Th) 1 and Th17 phenotypes. Th1 and Th17 effector cells, via production of pro-inflammatory mediators, participate in the low-grade inflammation that leads to blood pressure elevation and end-organ damage. T regulatory lymphocytes, on the other hand, counteract hypertensive effects by suppressing innate and adaptive immune responses. The present review summarizes and discusses the adaptive immune mechanisms that participate in the pathophysiology in hypertension.

Blood pressure

Adaptive immunity

Inflammation

T effector lymphocytes

T regulatory lymphocytes

Cytokines

Conclusion

Experimental and clinical evidence discussed in this review strongly suggests that adaptive immunity, represented by T effector and regulatory lymphocyte subsets, plays a dual role in hypertension (Figure 2). Increased sympathetic outflow as a consequence of stimulation of the CNS by hypertensive stimuli may result in mild blood pressure elevation, causing tissue injury and formation of neoantigens2 and/or damage-associated molecular patterns (DAMPs).80 Activation of innate APCs by DAMPs, or by pathogen-associated molecular patterns (PAMPs) generated in response to low-grade infection,80,81 and direct stimulation by CNS, may be the cause of activation of CD4+, and perhaps CD8+, T effector lymphocytes, and differentiation of CD4+ T cells towards pro-inflammatory Th1/Th17 phenotypes.41 Th1/Th17 effector lymphocytes contribute to the progression of hypertension by producing pro-inflammatory mediators, including ROS, IFN-γ, TNF-α, and IL-17, to promote low-grade inflammation.24,41,42,51,52 T regulatory lymphocytes, on the other hand, counteract hypertensive abnormalities by suppressing innate and adaptive immune responses, perhaps by secreting IL-10.65–71 As such, circulating levels of Tregs or their immune-suppressive activity may be affected in hypertension.

Resveratrol, an antioxidant found in red wine presented since 2003 presented for its potential to lower risk for cardiovascular disease and neurodegeneration by increasing cell survival and slowing aging: 2014 Study – Diet rich in resveratrol offers no health boost

Reporter: Aviva Lev-Ari, PhD, RN

Related to this study are other articles published in this Open Access Online Journal, including:

Abstract

In diverse organisms, calorie restriction slows the pace of ageing and increases maximum lifespan. In the budding yeastSaccharomyces cerevisiae, calorie restriction extends lifespan by increasing the activity of Sir2 (ref. 1), a member of the conserved sirtuin family of NAD+-dependent protein deacetylases2, 3, 4, 5, 6. Included in this family are SIR-2.1, a Caenorhabditis elegansenzyme that regulates lifespan7, and SIRT1, a human deacetylase that promotes cell survival by negatively regulating the p53 tumour suppressor8, 9, 10. Here we report the discovery of three classes of small molecules that activate sirtuins. We show that the potent activator resveratrol, a polyphenol found in red wine, lowers the Michaelis constant of SIRT1 for both the acetylated substrate and NAD+, and increases cell survival by stimulating SIRT1-dependent deacetylation of p53. In yeast, resveratrol mimics calorie restriction by stimulating Sir2, increasing DNA stability and extending lifespan by 70%. We discuss possible evolutionary origins of this phenomenon and suggest new lines of research into the therapeutic use of sirtuin activators.

Dr. David Sinclair, now a professor of genetics at Harvard Medical School. He and his colleagues discovered in 2003 that resveratrol could increase cell survival and slow aging in yeast (and later in mice) by activating a “longevity” gene known as SIRT1. Since then, we’ve learned that resveratrol can help

prevent skin cancer in mice;

protect against high blood pressure, heart failure, and heart disease in mice;

But the dose of resveratrol administered in experiments is always much higher than you’d normally consume in a daily diet. “You would need to drink a hundred to a thousand glasses of red wine to equal the doses that improve health in mice,” says Dr. Sinclair, who was named one of this year’s Time magazine 100 Most Influential People for his anti-aging research. He wasn’t surprised about the results in the JAMA Archives study.

Still, the disappointing results don’t mean that resveratrol and other molecules like it won’t help extend the lifespan or protect against the development of aging-related diseases. Dr. Sinclair points out that drug companies have now created thousands of new synthetic molecules, “that are up to a thousand times better than resveratrol. They prevent cardiovascular disease and neurodegeneration. They also extend lifespan in mice.”

The molecules don’t have catchy names yet—with current such as SRT1720 and SRT2104—but they’re showing promising results in mice. Dr. Sinclair is again helping to pioneer much of this research.

Importance Resveratrol, a polyphenol found in grapes, red wine, chocolate, and certain berries and roots, is considered to have antioxidant, anti-inflammatory, and anticancer effects in humans and is related to longevity in some lower organisms.

Objective To determine whether resveratrol levels achieved with diet are associated with inflammation, cancer, cardiovascular disease, and mortality in humans.

Design Prospective cohort study, the Invecchiare in Chianti (InCHIANTI) Study (“Aging in the Chianti Region”), 1998 to 2009 conducted in 2 villages in the Chianti area in a population-based sample of 783 community-dwelling men and women 65 years or older.

Results Mean (95% CI) log total urinary resveratrol metabolite concentrations were 7.08 (6.69-7.48) nmol/g of creatinine. During 9 years of follow-up, 268 (34.3%) of the participants died. From the lowest to the highest quartile of baseline total urinary resveratrol metabolites, the proportion of participants who died from all causes was 34.4%, 31.6%, 33.5%, and 37.4%, respectively (P = .67). Participants in the lowest quartile had a hazards ratio for mortality of 0.80 (95% CI, 0.54-1.17) compared with those in the highest quartile of total urinary resveratrol in a multivariable Cox proportional hazards model that adjusted for potential confounders. Resveratrol levels were not significantly associated with serum CRP, IL-6, IL-1β, TNF, prevalent or incident cardiovascular disease, or cancer.

Conclusions and Relevance In older community-dwelling adults, total urinary resveratrol metabolite concentration was not associated with inflammatory markers, cardiovascular disease, or cancer or predictive of all-cause mortality. Resveratrol levels achieved with a Western diet did not have a substantial influence on health status and mortality risk of the population in this study.

Research may lead to improved outcomes for large number of patients who previously had limited therapeutic options.

Scientists funded by the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health have found that a greater number of patients with coronary artery disease may benefit from coronary artery bypass graft (CABG) surgery than previously thought.

CABG — a surgical procedure to help improve blood flow to the heart by bypassing arteries clogged with cholesterol plaques — was thought to be too risky for patients with the long-term effects of coronary artery disease: left ventricular dysfunction (when the left side of the heart is unable to pump normally) and heart failure. Studies of the safety and effectiveness of CABG in the 1970s excluded most patients with these two conditions. The procedure was typically used to relieve angina, or chest pain.

“With limited data showing any benefit for patients with left ventricular dysfunction and heart failure, physicians and patients were less likely to engage in such an invasive, and thus risky, procedure as CABG for diagnosis and treatment,” said lead author Eric J. Velazquez, MD, FACP, FACC, FASE, FAHA, of Duke University Medical Center. “Patients with these conditions largely received medical therapy alone and had poor outcomes.”

Dr. Velazquez and his team conducted a five-year global, randomized controlled clinical trial, called the Surgical Treatment for Ischemic Heart Failure (STICH) study, and a five-year extension study (STICHES(link is external)), to evaluate whether CABG plus guideline-directed medical therapy had a durable benefit over medical therapy alone for patients with coronary artery disease and left ventricular dysfunction. The researchers found that CABG added to medical therapy led to significantly lower rates of death and hospitalization among patients with coronary artery disease, left ventricular dysfunction, and heart failure.

“Our results usher in a new era in the treatment of coronary artery disease because we now have evidence that with CABG and medical therapy, there is a 16 percent reduction in the risk of death from any cause over 10 years,” Dr. Velazquez said.

He added that there is also a median survival benefit of nearly a year and a half, and that he and his team saw that the addition of CABG to medical therapy prevented a death from any cause for every 14 patients they treated. Their data further suggest that the reduction in the risk of death could be even greater in real-world practice.

“Conducting this trial was critically important to determine in a scientifically rigorous study that CABG improves survival for individuals with coronary artery disease and compromised left ventricular function,” said NHLBI Director Gary H. Gibbons, MD. “The current 10-year follow-up provides new important insights about patient subgroups that are more likely to benefit from CABG as compared to medical therapy alone. As such, we now have a solid evidence base to inform patient care and the future development of clinical practice recommendations.”

Dr. Velazquez noted that the results are particularly important because the prevalence of left ventricular dysfunction and heart failure is expected to increase to approximately 8 million individuals by 2030 in the U.S. alone. The increase in the projected prevalence is a result of advances in the management of cardiovascular disease and its risk factors, increasingly transforming coronary artery disease into a chronic disease with long-term effects such as left ventricular dysfunction and heart failure.

George Sopko, MD, MPH, the program director in NHLBI’s Division of Cardiovascular Sciences who administered the study grant, added that this investigation, published in The New England Journal of Medicine (April 2016), is one of only a few cardiovascular trials with 10 years of follow-up and with approximately 98 percent of the patients followed throughout the study period.

“It is unusual to have this quality of follow-up for so long,” said Dr. Sopko. “It speaks to the rigor of the results.” He added that the results are very generalizable, as the study included a diverse patient population spread across 22 countries and various health systems.

Efficacy and Tolerability of PCSK9 Inhibitors by Patients with Muscle-related Statin Intolerance – New Cleveland Clinic study published in JAMA 4/2016

Curators: Larry H. Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

Medical Interpretation of Study Results and the Pharmacological Treatment Context of PCSK9 Inhibitors

Author: Larry H. Bernstein, MD, FCAP

The Rausse-3 Clinical Trial accompanied by editorial has been published in the Apr 3, 2016 issue of JAMA comparing toleration to and efficacy of Evolocumab vs Ezetimibe in patients with Statin-related muscle intolerance.

The very long-term outcomes reported for early statin primary prevention trials17,18are impressive. The Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) randomized patients with hypertension and multiple risk factors to receive atorvastatin (10 mg daily) or to placebo and was stopped after a median follow-up of 3.3 years because of benefit.17 Approximately 8 years later, 11 years after randomization, total mortality, cardiovascular mortality, and noncardiovascular mortality were all significantly reduced in patients who had been in the statin group. Among patients with statin intolerance related to muscle-related adverse effects, the use of evolocumab compared with ezetimibe resulted in a significantly greater reduction in LDL-C levels after 24 weeks. Whether PCSK9 inhibitors will have the same impressive long-term outcomes will not be known for many years.

Importance Muscle-related statin intolerance is reported by 5% to 20% of patients.

Design, Setting, and Participants Two-stage randomized clinical trial including 511 adult patients with uncontrolled low-density lipoprotein cholesterol (LDL-C) levels and history of intolerance to 2 or more statins enrolled in 2013 and 2014 globally. Phase A used a 24-week crossover procedure with atorvastatin or placebo to identify patients having symptoms only with atorvastatin but not placebo. In phase B, after a 2-week washout, patients were randomized to ezetimibe or evolocumab for 24 weeks.

Conclusions and Relevance Among patients with statin intolerance related to muscle-related adverse effects, the use of evolocumab compared with ezetimibe resulted in a significantly greater reduction in LDL-C levels after 24 weeks. Further studies are needed to assess long-term efficacy and safety.

Administration of HMG-CoA reductase inhibitors (statins) to reduce levels of low-density lipoprotein cholesterol (LDL-C) represents an essential component of contemporary strategies to reduce morbidity and mortality from atherosclerotic vascular disease.1 However, a significant proportion of patients with clinical indications for statin treatment report inability to tolerate evidence-based doses, most commonly because of muscle-related adverse effects.2 These patients typically report muscle pain or weakness when treatment is initiated or dosage increased and relief when the drug is discontinued or the dosage reduced. Although some patients with statin-associated muscle symptoms experience marked elevation in serum creatine kinase (CK) levels, most do not. Accordingly, diagnosis of this disorder remains largely subjective, based on the presence of patient-reported symptoms.3The incidence of similar symptoms in placebo-treated patients has resulted in skepticism about the true incidence of statin intolerance.

Patients with muscle-related intolerance often refuse to take statins despite elevated LDL-C levels and a high risk of major cardiovascular events. Current management may include very low or intermittent administration of statins or use of ezetimibe, but these strategies seldom achieve the greater than 50% reduction recommended by current guidelines.1,4,5 Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors markedly lower LDL-C levels and have shown potential as an alternative therapy for patients who experience intolerable adverse effects during statin therapy.6– 8 Currently available data suggest that muscle-related adverse effects are uncommon with PCSK9 inhibitors, even in patients with a history of such symptoms, but prior trials relied exclusively on medical history to document statin intolerance.

The GAUSS-3 (Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects 3) trial was designed as a 2-stage randomized clinical trial to first identify patients with statin-induced muscle symptoms during a placebo-controlled statin rechallenge procedure and subsequently to compare the effectiveness and tolerability of 2 nonstatin therapies—ezetimibe or evolocumab, a recently approved PCSK9 inhibitor.

Figure 2.

Time to First Occurrence of a Muscle-Related Adverse Effect Resulting in Discontinuation of Study Drug During Period 1 and Period 2 of Phase A, GAUSS-3 Trial

The two curves compare phase 1 versus phase 2 with the first showing a separation at about day 60 and the second at about day 18. The hazard ratios are 1.34 vs 1.96 for cumulative event probability with p < 0.02 vs 0.001.

Statin intolerance related to muscle symptoms represents a major unresolved challenge to the delivery of optimal cardiovascular care. The reported incidence of statin-associated muscle symptoms in observational studies ranges from 5% to 29% of treated patients, varying by statin and dose.2 Often, despite multiple attempts to find a statin regimen acceptable to the patient, practitioners resort to less effective therapies. Alternative approaches typically include use of ezetimibe or administration of statins intermittently or at dosages below the approved starting dose.4,5,12 These alternative therapeutic strategies provide less LDL-C reduction than recommended by current practice guidelines and result in higher LDL-C levels than most practitioners consider acceptable for optimal reduction of cardiovascular risk.

Both coprimary end points showed a 16.7% reduction with ezetimibe and a more than 50% reduction with evolocumab. These reductions in LDL-C levels are consistent with current labeling for both products. Despite very high baseline values, the LDL-C goal of less than 70 mg/dL was achieved in nearly 30% of evolocumab-treated patients and 1.4% of ezetimibe-treated patients (Table 3). The LDL-C reduction for both drugs was stable by 4 weeks and sustained during the course of the 24 weeks of treatment (Figure 3).

Because some patients cannot tolerate statins, the need for alternative LDL-C–lowering strategies in such patients is self-evident. Previous trials have suggested that PCSK9 inhibitors are effective at lowering LDL-C levels and well tolerated by patients with a history of statin-associated muscle symptoms.6– 8 The studies did not use a placebo-controlled statin rechallenge procedure to identify the presence of statin intolerance.

To our knowledge, the GAUSS-3 trial represents the largest and most comprehensive study using a blinded rechallenge procedure to assess the ability of patients with a history of muscle-related adverse effects to tolerate statins. The trial provides insights into the time course of statin-associated muscle-related adverse effects. As shown in Figure 2A, initial randomization to either atorvastatin or placebo in phase A resulted in similar rates of muscle symptoms during the first 50 days, with a modest increase in occurrence with atorvastatin near the end of the 10-week exposure (HR, 1.34 [95% CI, 1.05 to 1.71]; P = .02). After crossover to period 2, larger numbers of patients experienced symptoms in the atorvastatin treatment group, with differences in event rates occurring relatively early (HR, 1.96 [95% CI, 1.44 to 2.66]; P < .001) (Figure 2B).

1Cleveland Clinic, Cleveland, Ohio2University of Amsterdam Faculty of Medicine, Amsterdam, the Netherlands3Amgen Inc, Thousand Oaks, California4School of Medicine at Mount Sinai, New York, New York5Flinders University, Bedford Park, SA, Australia6University of Glasgow, Glasgow, United Kingdom7Clinical Trial Service Unit, University of Oxford, Oxford, United Kingdom8Epidemiological Services Unit, University of Oxford, Oxford, United Kingdom9University Hospital of Paris 6, Paris, France10Charles University in Prague, Prague, Czech Republic11General University Hospital in Prague, Prague, Czech Republic12David Geffen School of Medicine at the University of California, Los Angeles13Baylor College of Medicine, Houston, Texas14Center for Endocrinology, Diabetes and Preventive Medicine, University of Cologne, Cologne, Germany15Metabolic and Atherosclerosis Research Center, Cincinnati, Ohio

Design, Setting, and Participants Two-stage randomized clinical trial including 511 adult patients with uncontrolled low-density lipoprotein cholesterol (LDL-C) levels and history of intolerance to 2 or more statins enrolled in 2013 and 2014 globally. Phase A used a 24-week crossover procedure with atorvastatin or placebo to identify patients having symptoms only with atorvastatin but not placebo. In phase B, after a 2-week washout, patients were randomized to ezetimibe or evolocumab for 24 weeks.

Conclusions and Relevance Among patients with statin intolerance related to muscle-related adverse effects, the use of evolocumab compared with ezetimibe resulted in a significantly greater reduction in LDL-C levels after 24 weeks. Further studies are needed to assess long-term efficacy and safety.

Newly released trial data from Eli Lilly’s 12,000-patient study on its cholesterol drug evacetrapib showed no clinical benefit in reducing rates of heart attack, stroke, or cardiovascular disease, despite seemingly positive effects on lipid levels, the New York Times reports.

Presented at the annual meeting of the American College of Cardiology, the data gave further insight into why Eli Lilly abruptly halted the phase 3 trial in October 2015. At the time, Lilly said there was a low probability the study’s primary endpoint would be reached.

Evacetrapib is one version of a class of cholesterol drugs known as CTEP inhibitors, which work by boosting the levels of HDL cholesterol, or “good” cholesterol. Two other CTEP inhibitors have failed while one, being developed by Merck, is still being studied.

While Lilly’s announcement in October dashed hopes for evacetrapib, the newly announced full data only adds to the puzzle. The 12,000 patients studied were randomized and put into either a evacetrapib group or a placebo group. Average HDL levels of those on evacetrapib rose by about 130% while LDL, or “bad” cholesterol, levels fell by about 35%.

But these results did not translate into any meaningful clinical benefit. Rates of heart attack, stroke, and death from cardiovascular disease (CVD) were nearly identical in both groups, according to the New York Times.

CTEP inhibitors had generated a lot of excitement because of their potential to be an alternative to statins, a standard treatment for CVD. Some patients cannot tolerate statins, spurring the search for new and more effective treatment options.

Eli Lilly thought the drug could reach blockbuster status before its lack of efficacy brought the trial to a close. As the third failed CTEP inhibitor, evacetrapib’s ineffectiveness on CVD may undermine development interest in the entire class.

Another new type of cholesterol drugs, known as PCSK9 inhibitors, are already on the market for the treatment of high cholesterol. However, their effect on CVD is still being studied.

–No benefit with evacetrapib despite increase in HDL and decrease in LDL

The fat lady hasn’t sung, the referee hasn’t counted up to 10, but it’s sure not looking good for the once highly promising class of drugs known as the CETP inhibitors.

Bang the Drum Slowly, and Play the Fife Lowly

Following the crash and burn of torcetrapib in the ILLUMINATE trial and dalcetrapib in the dal-OUTCOMES trial, we now have the full obituary details on a third CETP inhibitor, Lilly’s evacetrapib. The one remaining hope for the class lies with Merck’s anacetrapib, which continues to be studied in the ongoing REVEAL study.

12,000 high risk patients were randomized to evacetrapib or placebo. Evacetrapib, as anticipated, had a potent effect on lipids levels. HDL was dramatically increased by 130%, from 46 mg/dL in the placebo group to a whopping 104 mg/dL in the evacetrapib group. LDL levels also underwent a big change, from 84 mg/dL in the placebo group to 55 mg/dL in the evacetrapib group. One surprising finding was that the hsCRP increased by 4.6% under evacetrapib but decreased by 8% in the placebo group.

But the lipid results did not translate into clinical benefit. The primary endpoint (CV death, MI, stroke, coronary revascularization or hospitalization for unstable angina) was nearly identical in the two groups: 12.8% in the evacetrapib group versus 12.7% in the placebo group. There were no significant differences in any of the secondary endpoints.

There were some additional surprising findings. Investigator-reported hypertension was significantly increased with evacetrapib (11.4% versus 10.1% for placebo, P<0.05). There was a small but statistically significant difference of 1 mmHg in mean systolic blood pressure during the trial (132 with evacetrapib and 131 with placebo).

“Here we’ve got an agent that more than doubles the levels of good cholesterol and lowers bad cholesterol and yet has no effect on clinical events,” said Nicholls, in a press release. “We were disappointed and surprised by the results.”

“The failure of decreases in LDL-C to result in an overall morbidity-mortality benefit emphasizes the limitations of surrogate endpoints,” Nicholls said in his talk. “The findings continue to challenge the hope that CETP inhibition might successfully address residual CV risk.”

The failure of the CETP trials has led many experts to abandon the idea that simply raising HDL levels would prove to be beneficial. Opinion is now divided whether or not HDL has an important independent mechanistic role. Some believe that HDL still plays an important role but the HDL number is less important than measurements of its function.

Elliott Antman, MD, (Brigham and Women’s Hospital) cautioned against any interpretation suggesting that the results in any way seriously threaten the LDL hypothesis. He said that the relatively short followup in the study (less than 3 years) raises concerns that there was not enough time for any benefit from LDL reduction to emerge. The changes in CRP, though statistically significant, were also far too small to raise a clinical concern, he said.

I asked Sekar Kathiresan (Massachusetts General Hospital) whether the ACCELERATE results have any bearing on the LDL hypothesis. Here is his extended response:

Epidemiological, experimental, human genetic, and treatment studies all are consistent with LDL being a causal factor for atherosclerosis. The treatment evidence comes from two LDL lowering mechanisms: statins and ezetimibe. A third LDL lowering mechanism (PCSK9i) has suggestive evidence.